Submissions for variant NM_001048174.2(MUTYH):c.1429T>G (p.Cys477Gly)

gnomAD frequency: 0.00001  dbSNP: rs876659488

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229418	SCV000285935	uncertain significance	Familial adenomatous polyposis 2	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 505 of the MUTYH protein (p.Cys505Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 238339). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000566512	SCV000666475	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-01	criteria provided, single submitter	clinical testing	The p.C505G variant (also known as c.1513T>G), located in coding exon 15 of the MUTYH gene, results from a T to G substitution at nucleotide position 1513. The cysteine at codon 505 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587590	SCV000697682	uncertain significance	not provided	2016-07-15	criteria provided, single submitter	clinical testing	Variant summary: The MUTYH c.1513T>G (p.Cys505Gly) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP), nor has it been, to our knowledge, reported in affected individuals via publications. However, a clinical laboratory does cite the variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information is available.
Color Diagnostics, LLC DBA Color Health	RCV000566512	SCV000905261	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-23	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 505 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/243216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587590	SCV001134468	uncertain significance	not provided	2019-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000587590	SCV001991417	uncertain significance	not provided	2023-03-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11092888, 23108399)
Revvity Omics, Revvity	RCV000229418	SCV003817131	uncertain significance	Familial adenomatous polyposis 2	2019-12-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000229418	SCV004198898	uncertain significance	Familial adenomatous polyposis 2	2024-02-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000229418	SCV004824542	uncertain significance	Familial adenomatous polyposis 2	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 505 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/243216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.